Sobieraj Diana M, White C Michael, Coleman Craig I
University of Connecticut School of Pharmacy, Storrs, Connecticut, USA.
Clin Ther. 2008 Aug;30(8):1416-25. doi: 10.1016/j.clinthera.2008.08.004.
Several clinical trials have evaluated the benefits associated with adding an inhaled corticosteroid (ICS) to a long-acting bronchodilator in the treatment of severe or very severe (stage III or IV) chronic obstructive pulmonary disease (COPD).
We conducted a meta-analysis to elucidate the benefits and risks associated with adjunctive ICS treatment in patients with severe or very severe COPD.
A systematic literature search of MEDLINE, EMBASE, and the Cochrane Collaboration's Central Register of Controlled Clinical Trials (from initiation through April 2008) was conducted by 2 investigators working independently. A search strategy using key medical subject headings and text key words was performed using the Cochrane Collaboration's Highly Sensitive Search Strategy for MEDLINE and the McMaster University Health Information Research Unit EMBASE search strategy. To be included in this meta-analysis, studies had to be randomized controlled trials; compare the use of ICS in combination with long-acting beta-agonists (LABAs) or tiotropium with long-acting bronchodilator monotherapy; include only subjects with COPD and forced expiratory volume in 1 second (FEV(1)) <80% and an FEV(1)/forced vital capacity ratio <70%; follow up patients for a minimum of 24 weeks; and report data on either mortality or exacerbations. We evaluated 3 efficacy end points (exacerbations, mortality, and change in St. George's Respiratory Questionnaire [SGRQ] score), 2 tolerability end points (pneumonia and oral candidiasis), and study withdrawals. Rate ratios and relative risks (RRs) were calculated using a random effects model. Statistical heterogeneity was addressed using the Q statistic and I(2) value. The Egger weighted regression statistic and visual inspection of funnel plots were used to assess publication bias.
A total of 9 studies met the inclusion criteria (N = 7,992 subjects). Seven trials provided exacerbation rates and 8 trials provided data on overall mortality. Change in SGRQ score from baseline was reported in 6 trials while pneumonia and oral candidiasis were reported in 5 and 6 studies, respectively. The incidence of patient withdrawal was reported in 8 studies. Exacerbations (rate ratio, 0.82; 95% CI, 0.72-0.92) and SGRQ score (weighted mean difference, -1.98 points; 95% CI, -2.56 to -1.40) were reduced with adjunctive ICS treatment but mortality was not affected (rate ratio, 0.86; 95% CI, 0.73-1.02). Both pneumonia (RR, 1.68; 95% CI, 1.28-2.21) and oral candidiasis (RR, 2.93; 95% CI, 1.94-4.42) were increased with adjuvant ICS treatment. Patient study withdrawal for any reason (RR, 0.83; 95% CI, 0.74- 0.93) was less likely with adjuvant ICS treatment. On visual inspection of the funnel plots, publication bias could not be ruled out for either efficacy or tolerability end point analysis. However, inspection of the Egger weighted regression statistic suggested the low likelihood of publication bias for all end points.
Addition of an ICS to a LABA was associated with a reduced risk for exacerbations but an increased risk for pneumonia and oral candidiasis compared with long-acting bronchodilator monotherapy in this meta-analysis of 9 randomized controlled trials. While measured patient-perceived health and well-being increased to a statistically significant level, this did not translate into a clinically meaningful level for all patients with combination treatment. Lower risk of study withdrawal was observed in adjuvant ICS patients. The benefits and risks associated with adjunctive ICS treatment will need to be assessed when making decisions regarding its use.
多项临床试验评估了在长效支气管扩张剂基础上加用吸入性糖皮质激素（ICS）治疗重度或极重度（Ⅲ期或Ⅳ期）慢性阻塞性肺疾病（COPD）的益处。
我们进行了一项荟萃分析，以阐明重度或极重度COPD患者辅助使用ICS治疗的益处和风险。
由2名独立工作的研究人员对MEDLINE、EMBASE和Cochrane协作网临床对照试验中心注册库（从建库至2008年4月）进行系统文献检索。采用Cochrane协作网针对MEDLINE制定的高敏感性检索策略和麦克马斯特大学健康信息研究组的EMBASE检索策略，运用关键医学主题词和文本关键词进行检索。纳入本荟萃分析的研究必须为随机对照试验；比较ICS联合长效β受体激动剂（LABA）或噻托溴铵与长效支气管扩张剂单药治疗；仅纳入COPD且第1秒用力呼气容积（FEV₁）<80%、FEV₁/用力肺活量比值<70%的受试者；对患者进行至少24周的随访；并报告死亡率或急性加重的数据。我们评估了3个疗效终点（急性加重、死亡率、圣乔治呼吸问卷[SGRQ]评分变化）、2个耐受性终点（肺炎和口腔念珠菌病）以及研究退出情况。采用随机效应模型计算率比和相对危险度（RR）。使用Q统计量和I²值处理统计异质性。采用Egger加权回归统计量和漏斗图的直观检查评估发表偏倚。
共有9项研究符合纳入标准（N = 7992名受试者）。7项试验提供了急性加重率，8项试验提供了总死亡率数据。6项试验报告了SGRQ评分相对于基线的变化，5项和6项研究分别报告了肺炎和口腔念珠菌病的情况。8项研究报告了患者退出研究的发生率。辅助使用ICS治疗可降低急性加重（率比，0.82；95%CI，0.72 - 0.92）和SGRQ评分（加权平均差，-1.98分；95%CI，-2.56至-1.40），但未影响死亡率（率比，0.86；95%CI，0.73 - 1.02）。辅助使用ICS治疗会增加肺炎（RR，1.68；95%CI，1.28 - 2.21）和口腔念珠菌病（RR，2.93；95%CI，1.94 - 4.42）的发生率。辅助使用ICS治疗使患者因任何原因退出研究的可能性降低（RR，0.83；95%CI，0.74 - 0.93）。通过漏斗图的直观检查，在疗效或耐受性终点分析中均不能排除发表偏倚。然而，Egger加权回归统计量的检查表明所有终点存在发表偏倚的可能性较低。
在这项对9项随机对照试验的荟萃分析中，与长效支气管扩张剂单药治疗相比，LABA加用ICS可降低急性加重风险，但会增加肺炎和口腔念珠菌病的风险。虽然患者自我感知的健康和幸福感在统计学上有显著提高，但对于所有联合治疗的患者来说，这并未转化为具有临床意义的水平。辅助使用ICS治疗的患者退出研究的风险较低。在决定是否使用辅助ICS治疗时，需要评估其相关的益处和风险。
